Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via mediating histone acetylation

Abstract Background We aim to connect directly the energy metabolism and epigenetics for heart therapy. Energy is fundamental for all living organisms and the heart is most sensitive to energy supply and production. One key response to energy status is to use one carbon or two carbon moieties derived from metabolites to change chromatin structure by methylation and acetylation and regulate gene expression. In particular, acetyl-CoA is a building block for energy metabolism and histone acetylation. However, the acetyl-CoA-mediated regulatory machinery integrating metabolic pathways and chromatin modifications has been under-explored in heart repair and protection. Methods We conducted a screen of energy metabolites in swift production of acetyl-CoA and cardiac repair after ischemic reperfusion injury (I/R). We next examined the relationships between acetyl-CoA production, histone acetylation and heart repair after I/R. Cellular, molecular, and epigenetic studies were conducted to determine the metabolic/epigenetic network involved in executing the energy metabolite-mediated heart protection. Results We identified that acetate, pyruvate, and octanoic acid (8C), but not citrate and nonanoic acid, improved heart function in I/R rats. In particular, 8C administration resulted in the most significant heart functional recovery. In a more clinically relevant setting, 8C injection at the time of reperfusion 45 minutes after left anterior descending coronary (LAD) ligation showed comparable repair effect to that of 8C administration before LAD ligation, suggesting that 8C could be a very effective metabolic natural product to treat I/R injury. Mechanistically, 8C promoted histone acetylation in cardiomyocytes (CM) after I/R injury and inhibited CM apoptosis by activating expression of anti-oxidant genes HO1, NQO1 and SOD2. We further established that the 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a. Conclusions Our data demonstrate that administration of 8C dramatically improves cardiac function through metabolic acetyl-CoA-mediated histone acetylation. This study elucidates an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a in stimulating histone acetylation and anti-oxidative stress gene expression to combat heart injury. Our study provides a framework for developing novel heart repair and protection strategies at the interface of metabolism and epigenetics.